Saturday, July 06, 2013 2:22:16 PM
Entdoc, here’s a bunch of stuff on Betabodies. Re: your question about Peregrine’s patent control of them going forward, pay particular attention to:
1) Patent app# 20060228299 ( filed 1-24-2006, pub 10-12-2006, inventors: P.Thorpe, T.Luster, S.King), ”Constructs Binding to Phosphatidylserine and Their Use in Disease Treatment", assigned to both Peregrine & UTSW
AND
2) Peregrine’s 7-9-07 PR, where they obtained “worldwide exclusive rights” to “Clipped B2GP1” (or “Nicked B2GP1”) from M.D.Anderson (invented by MDA’s Dr. Alan Schroit, PPHM SRB member) - this is the basis for PS-targeting “BetaBodies” – ie, 2nd-gen. Bavi…
= = = = = = = = = = = = =
BETABODIES – Peregrine’s Next Generation PS-Targeting Cancer Therapeutics
…“The betabody KL15 consists of a fusion of domains I & V from the phosphatidylserine (PS) binding protein B2GP1 with the CH2 & CH3 constant domains of a mouse IgG2a antibody. Betabodies bind to PS directly, are smaller in size (100 vs. 250KDa), and have a longer serum half-life (~5days) than natural antibodies (Bavi=~1day).”
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =
AACR’13 4-9-13 Poster #4326: “Phosphatidylserine-Targeting ‘Beta bodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1
1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD
Session: Antibody Therapeutics & Novel Delivery Technologies
ABSTRACT:
“Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse B2-glycoprotein I (B2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have the following advantages: they bind directly to PS, and do not require a cofactor protein (B2GP1) for binding; they can be made fully human; they are smaller in size (100 KDa); and they have slower blood clearance rates. A construct was generated that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had a B-phase blood half-life of approximately 5 days after intravenous injection into mice as compared with 1 day for a murine version of bavituximab, 2aG4. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.”
- - - - - - - - - - -
PPHM 4-10-13 PRESS RELEASE COMMENTS RE: #4326:
”Researchers also presented details of new PS-binding constructs(4). Termed "betabodies”, the molecules consist of the PS-binding domain of the serum protein B2-glycoprotein I (B2GPI), fused to the constant region of an antibody. Betabodies bind to PS directly, are smaller in size and have a longer serum half-life than natural antibodies. Early studies indicate that betabodies hold potential as next-generation PS-binding agents that have the potential to be used for a broad number of applications including antibody-drug conjugates and next generation therapeutics for oncology and infectious diseases."
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519
PDF of AACR’13 Poster #4326 “Betabodies”:
http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf
- - - - -
Snapshot of Peregrine’s AACR’13 BETABODIES Poster – from http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html
=> http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf
AACR’13 4-9-13/Tue Poster #4326: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1
1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD
Session: Antibody Therapeutics & Novel Delivery Technologies
= = = = = = = = = = = = =
AACR 2012, Chicago
AACR’12 #4632 4-3-12: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, Philip E. Thorpe 1
1 UTSW-MC/Dallas
2 Human Genome Sciences, Rockville, MD [<=Troy Luster, Senior Scientist , HGSI – formerly a member of Dr. Thorpe’s Lab at UTSW***]
Track: Antibody & Microenvironmental Therapies
ABSTRACT:
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse B2-glycoprotein I (B2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have advantages over bavituximab. They bind directly to PS, whereas bavituximab requires a cofactor protein (B2GP1) for binding; they can be made fully human; they are smaller in size (100KDa vs. 250KDa for the bavituximab:B2GP1 complexes); and they have slower blood clearance rates. Many different constructions of betabodies were tested, each having different orientations, domains, and glycosylation patterns. Constructs were identified that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had B-phase blood half-lives of approximately 7 days after intravenous injection into mice as compared with 2 days for a murine version of bavituximab. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=703cc4da-b090-4a6a-acd6-1af3a1da646c&cKey=beefac61-3234-4c92-bd9c-72cd17517273
[***NOTE: Troy Luster was a member of Dr. Thorpe's Lab at UTSW before joining HGSI...
EX: American Cancer Society - Grants in effect on 1/1/2006...
Title: “Radiation-Guided Vascular (CCE) Targeting of Prostate Cancer”
1/1/2006-12/31/2008 $138,000 Grant# PF-06-004-01-CCE
To: Troy A. Luster, PhD, Mentor: Thorpe, Philip E., PhD, UTSW-MC/Dallas
Scientific Model Systems=10%, Treatment=90% Organ Sites: Prostate 100%
SEE: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=11443863
= = = = = = = = = = = = =
4-10-13 Piper Jaffray (Charles Duncan, PhD) comments on Peregrine’s Betabodies AACR’13 pre-clin. data:
http://oncology.healthace.com/041113/oncology_report_041113_s8.pdf
“Peregrine: Pre-clinical Data at AACR Points to Broader Phosphatidylserine Platform [ie, “Betabodies”]; Regulatory Clarity for Bavituximab in NSCLC Could Emerge This Year”
Pre-clinical investigators recently presented data at AACR from studies of bavituximab (Bavi) and a novel phosphatidylserine targeting fusion-protein construct "betabodies”. Data generated with the KL15 betabody indicate a ~5x longer half-life vs. the mouse Bavi, and localization to tumor vasculature and inflammatory cells in mice. We believe this data represents the tip of the spear of what may be a new platform with potentially superior performance and broader lipid-targeting applicability…
Betabodies a tested approach, applied to a novel target. The most impactful data presented at AACR, in our view, could be that describing the betabody fusion-protein. The betabody KL15 consists of a fusion of domains I & V from the phosphatidylserine (PS) binding protein beta2-glycoprotein 1 (B2GP1) with the CH2 & CH3 constant domains of a mouse IgG2a antibody. We note this is a somewhat similar approach to receptor-Fc fusions that can be used to bind soluble growth factors present in the blood stream, such Regeneron’s “trap” proteins that target molecules like VEGF and others. Due to the typical high-binding affinities between a receptor and its ligand, these constructs often possess high affinity as well as long durability due to the stability of the antibody domain.
= = = = = = = =PATENTS:
‘BETABODIES’ patent app #20060228299, filed 1-24-2006, pub 10-12-2006
"Constructs Binding to Phosphatidylserine and Their Use in Disease Treatment" ("Betabodies & Receptorbodies”)
Inventors: Philip E. Thorpe, Troy A. Luster, Steven W. King
Assignee1: BOARD OF REGENTS, UNIV. OF TEXAS SYSTEM, 201 W. 7TH ST, AUSTIN, TX
Assignee2: PEREGRINE PHARMACEUTICALS, INC., 14272 FRANKLIN AVE, TUSTIN, CA
USPTO: http://tinyurl.com/649986
ABSTRACT: “Disclosed are new phosphatidylserine binding constructs with surprising combinations of properties, and a range of diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine targets in disease and enhance their destruction, and can also specifically deliver attached imaging or therapeutic agents to the disease site. Also disclosed are methods of using the new construct compositions, therapeutic conjugates and combinations thereof in tumor vasculature targeting, cancer diagnosis and treatment, and for treating viral infections and other diseases.”
[0015] ReceptorBodies & BetaBodies: The invention first provides a range of phosphatidylserine binding construct compositions, in which the constructs comprise at least a first phosphatidylserine binding protein, polypeptide or receptor operatively attached to at least a first antibody Fc region. Joining a phosphatidylserine binding protein, polypeptide or "receptor" to an "antibody" Fc region gives rise to the terms "receptorbody" and "receptorbodies", which are used herein to refer to the phosphatidylserine-binding Fc constructs of the invention.
- - - - - - - - - - - - - - -MORE:
Dr. Thorpe's LAB TEAM (UTSW Hamon Center): http://tinyurl.com/yuxemu
…2013: Thorpe lab taken over by UTSW’s Dr. Rolf Brekken: http://www.utsouthwestern.edu/labs/brekken
Dr. Thorpe's Patents: GRANTED: http://tinyurl.com/m232k PENDING: http://tinyurl.com/845p2
Dr. Thorpe's Articles: http://tinyurl.com/csjsl Also see: http://www.researchgate.net/profile/Philip_Thorpe
Dr. Alan Schroit's Patents (MDA, PPHM SRB, “Clipped B2GP1”): GRANTED: http://tinyurl.com/n4pnk8p PENDING: http://tinyurl.com/mrf2nsb
DR. SCHROIT’s ARTICLES: http://tinyurl.com/lqbd8kt Also see: http://tinyurl.com/lx2p32b (MDA profile)
= = = = = = = = = = = = = = = = = = = =
PR 7-9-07: Peregrine Licenses MDA’s “Clipped B2GP1” (invented by MDA’s Dr. Alan Schroit, PPHM SRB member – this is the basis for PS-targeting “BetaBodies” – ie, 2nd-gen. Bavi)…
…Dr. Schroit: “Clipped forms of B2GP1 may represent an exciting new approach for anti-angiogenesis therapies, and I am pleased to be collaborating with Peregrine to further explore its clinical utility. The more we learn about this plasma protein, the more intriguing its role appears to be. The anti-angiogenic potential of B2GP1 was first identified by my lab in studies suggesting that it is a negative regulator of angiogenesis that can inhibit the growth of primary tumors and metastases. 1st-Gen. anti-angiogenesis agents have already demonstrated their value in some cancer and ophthalmology applications, and we are eager to learn more about the clinical potential of this new anti-angiogenesis approach."
“Peregrine Acquires Worldwide (Exclusive) Rights to Novel Anti-Angiogenesis Technology From M. D. Anderson Cancer Center”
• “all forms of ‘clipped’ (or nicked) Beta 2 Glycoprotein 1 (B2GP1) protein”
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21055309
Correct PR link: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=266033
= = = = = = = AACR2007 (1st ‘Betabodies’ mention):
#4089 (4-17-07) ”Fusion Proteins Composed of Mouse Igg2a Fc & Mouse B2GP1 Bind to Endothelial Cells with Exposed Phosphatidylserine” [‘BETABODIES’]
Troy A. Luster, Philip E. Thorpe - UTSW-MC/Dallas
FULL ABSTRACT (JBM 3-14-07 iHub): http://www.investorshub.com/boards/read_msg.asp?message_id=17860821
” A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane under normal conditions. We have previously shown that PS becomes exposed on the surface of viable endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, a murine monoclonal antibody (3G4) was developed. 3G4 specifically localizes to the vasculature of solid tumors and inhibits growth of murine and human tumor xenografts. A chimeric version of 3G4 (bavituximab) is currently in clinical trials for treatment of solid tumor malignancies.
Recently we determined that 3G4 recognizes PS through the formation of a complex with plasma protein beta-2-glycoprotein 1 (B2GP1) b2GP1 is a 50 kDa glycoprotein composed of five domains, including the positively charged domain V that binds anionic phospholipids. However, the interaction of b2GP1 with anionic phospholipids is weak under physiological conditions. Importantly, we demonstrated that 3G4 enhances the avidity of b2GP1 for membrane surfaces with exposed PS through the formation of multivalent 3G4/b2GP1/PS complexes. This increased avidity of b2GP1 for PS is likely responsible for targeting of 3G4 to tumor EC with exposed PS.
We report here the construction of recombinant fusion proteins composed of mouse IgG2a Fc and mouse b2GP1. The Fc region is fused to the N-terminus of full-length b2GP1 or domain V only. This orientation was chosen to avoid interference with the lipid binding region in domain V of b2GP1, which is located at the extreme C-terminus of the protein. These compounds are generated as dimers, linked via disulfide bonds in the hinge region of the Fc tags. The dimeric construction provides the increased avidity necessary for these compounds to bind EC with exposed PS; thus, they behave in vitro much like the 3G4/b2GP1 complexes described previously. These Fc-B2GP1 compounds [‘BETABODIES’] have potential as tumor therapeutic or imaging agents.”
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =
COMMENTARTY on Peregrine Licensing Clipped-B2GPI/’Betabodies’ from MDA in 7-2007:
7-9-2007 JBM, IHUB #15268
Bavituximab is an antibody, whose 2 "feet" (antigen binding regions) each need to grab one molecule of B2GPI in order to stick to PS. Bavituximab, (like many antiphospholipid antibodies found in people), needs a co-factor to stick to its target phospholipid. The feet of bavi stick to "domain 2" of B2GPI. B2GPI's "domain 5" is actually what sticks to PS, especially when you put together TWO B2GPI molecules - (which is what bavi does).
Bavituximab is a "beta-2-glycoprotein-I-dependent anti-phosphatidylserine antibody. Here's a simplified pic:
Now, after that was all understood, (which took some time, - please read paragraphs 233-255 of the most recent Thorpe/King/Luster patent application #20120164071, which I will paste at the bottom of this post. It's a great recap of the insights & discoveries that led to the current understanding of bavi and why it is not one of the 'bad ones')…
Anyway, after that was all understood, ideas for 2nd generation drugs became obvious, hence- BETABODIES.....
A "Betabody" is a kind of "pre-made" complex of bavi+ two B2GPI's. You see, when bavi gets put into your bloodstream, each bavi molecule needs to grab TWO B2GPI's in order to form that particular complex that is so attracted to PS. There is a finite amount of available B2GPI at any given time. There is a curve of diminishing returns that comes into play, - if too many bavi molecules were shot into you, a higher percentage of them would only find ONE B2GPI molecule, resulting in a bunch of bavi's floating around that can't find a 2nd B2GPI, which is a waste...
(Obviously one reason for all this intellectual property is to cover all the bases, the possible other ways to come up with recombinant molecules that do what bavi does)…
Anyway, the idea obviously came about of making that special complex in advance. If you can, (and you can), cut the 2 feet of an antibody off, and then glue 2 B2GPI molecules on where the feet used to be, you'd have that "bavi/two-B2GPI complex" all set up to go, in advance, and taking that bell-curve of PS binding out of play.
FURTHERMORE… If you'll read the most recent patent application#20120164071 [ http://tinyurl.com/y8xuur ], you'll see how important it is for PPHM to have gotten the rights for nicked B2GPI, in as much as it looks like another next generation drug may simply be two of the B2GPI's themselves linked together, or nicked bits or two of the PS-binding regions of B2GPI linked together, or any of who knows how many other possible combinations of various domains of B2GPI that can be designed to stick well to PS...
FOR INSTANCE - in the recent patent application, there's info on:
An artificial dimeric .beta.2GPI construct binds endothelial cells with exposed PS... The patent application, (the 'betabody' patent application) is a great read if you're interested. It would help folks see the connections/logic/progress between bavi, bit's of bavi, B2GPI, & various cleaved/nicked forms of B2GPI and all the possible combinations...
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21062715
7-9-2007 BIG-TARVY, IHUB #15268
Our Lead in Anti-PS field is Confirmed.
Jazz made the understatement of the year:
“FURTHERMORE.............
If you'll read the most recent patent application, YOU’LL SEE HOW IMPORTANT IT IS FOR PPHM TO HAVE GOTTEN THE RIGHTS FOR NICKED B2GPI, in as much as it looks like another next generation drug may simply be 2 of the B2GPI's themselves linked together, or nicked bits or 2 of the PS-binding regions of B2GPI linked together, or any of who knows how many other possible combinations of various domains of B2GPI that can be designed to stick well to PS...”
As Jazz points out, M.D. Anderson could have gone to any BP or BB and sold their B2GP1 innovations for big bucks as a way to circumvent PPHM’s monopoly in the anti-PS arena.
But they did not do this. Instead, they chose to ride the future of B2GP1 EXCLUSIVELY with PPHM. Was this because of:
• the headstart PPHM has in the clinic?
• or the unique properties of 3G4 as the ideal construct for B2GP1 to bind to?
• or the strength of PPHM’s anti-PS patent portfolio?
• or the strength of PPHM’s scientists and know-how in the anti-PS field?
It doesn’t really matter which of these reasons was the dominant reason for MDA’s decision. The point is that very credible scientists at MDA, owning rights to a key component of the ultimate anti-PS platform, chose to consolidate their technology with our technology.
When analyst coverage starts, today’s license will be presented as a major reason why the BP & BB barriers to entry in the anti-PS field are so high. It seems we now have a lock on both the first-generation and the 2nd-gen. lines of anti-PS drugs.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21070033
1) Patent app# 20060228299 ( filed 1-24-2006, pub 10-12-2006, inventors: P.Thorpe, T.Luster, S.King), ”Constructs Binding to Phosphatidylserine and Their Use in Disease Treatment", assigned to both Peregrine & UTSW
AND
2) Peregrine’s 7-9-07 PR, where they obtained “worldwide exclusive rights” to “Clipped B2GP1” (or “Nicked B2GP1”) from M.D.Anderson (invented by MDA’s Dr. Alan Schroit, PPHM SRB member) - this is the basis for PS-targeting “BetaBodies” – ie, 2nd-gen. Bavi…
= = = = = = = = = = = = =
BETABODIES – Peregrine’s Next Generation PS-Targeting Cancer Therapeutics
…“The betabody KL15 consists of a fusion of domains I & V from the phosphatidylserine (PS) binding protein B2GP1 with the CH2 & CH3 constant domains of a mouse IgG2a antibody. Betabodies bind to PS directly, are smaller in size (100 vs. 250KDa), and have a longer serum half-life (~5days) than natural antibodies (Bavi=~1day).”
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =
AACR’13 4-9-13 Poster #4326: “Phosphatidylserine-Targeting ‘Beta bodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1
1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD
Session: Antibody Therapeutics & Novel Delivery Technologies
ABSTRACT:
“Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse B2-glycoprotein I (B2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have the following advantages: they bind directly to PS, and do not require a cofactor protein (B2GP1) for binding; they can be made fully human; they are smaller in size (100 KDa); and they have slower blood clearance rates. A construct was generated that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had a B-phase blood half-life of approximately 5 days after intravenous injection into mice as compared with 1 day for a murine version of bavituximab, 2aG4. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.”
- - - - - - - - - - -
PPHM 4-10-13 PRESS RELEASE COMMENTS RE: #4326:
”Researchers also presented details of new PS-binding constructs(4). Termed "betabodies”, the molecules consist of the PS-binding domain of the serum protein B2-glycoprotein I (B2GPI), fused to the constant region of an antibody. Betabodies bind to PS directly, are smaller in size and have a longer serum half-life than natural antibodies. Early studies indicate that betabodies hold potential as next-generation PS-binding agents that have the potential to be used for a broad number of applications including antibody-drug conjugates and next generation therapeutics for oncology and infectious diseases."
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519
PDF of AACR’13 Poster #4326 “Betabodies”:
http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf
- - - - -
Snapshot of Peregrine’s AACR’13 BETABODIES Poster – from http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html
=> http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf
AACR’13 4-9-13/Tue Poster #4326: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1
1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD
Session: Antibody Therapeutics & Novel Delivery Technologies
= = = = = = = = = = = = =
AACR 2012, Chicago
AACR’12 #4632 4-3-12: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer”
Xianming Huang 1, Dan Ye 1, Troy Luster 2, Philip E. Thorpe 1
1 UTSW-MC/Dallas
2 Human Genome Sciences, Rockville, MD [<=Troy Luster, Senior Scientist , HGSI – formerly a member of Dr. Thorpe’s Lab at UTSW***]
Track: Antibody & Microenvironmental Therapies
ABSTRACT:
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse B2-glycoprotein I (B2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have advantages over bavituximab. They bind directly to PS, whereas bavituximab requires a cofactor protein (B2GP1) for binding; they can be made fully human; they are smaller in size (100KDa vs. 250KDa for the bavituximab:B2GP1 complexes); and they have slower blood clearance rates. Many different constructions of betabodies were tested, each having different orientations, domains, and glycosylation patterns. Constructs were identified that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had B-phase blood half-lives of approximately 7 days after intravenous injection into mice as compared with 2 days for a murine version of bavituximab. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=703cc4da-b090-4a6a-acd6-1af3a1da646c&cKey=beefac61-3234-4c92-bd9c-72cd17517273
[***NOTE: Troy Luster was a member of Dr. Thorpe's Lab at UTSW before joining HGSI...
EX: American Cancer Society - Grants in effect on 1/1/2006...
Title: “Radiation-Guided Vascular (CCE) Targeting of Prostate Cancer”
1/1/2006-12/31/2008 $138,000 Grant# PF-06-004-01-CCE
To: Troy A. Luster, PhD, Mentor: Thorpe, Philip E., PhD, UTSW-MC/Dallas
Scientific Model Systems=10%, Treatment=90% Organ Sites: Prostate 100%
SEE: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=11443863
= = = = = = = = = = = = =
4-10-13 Piper Jaffray (Charles Duncan, PhD) comments on Peregrine’s Betabodies AACR’13 pre-clin. data:
http://oncology.healthace.com/041113/oncology_report_041113_s8.pdf
“Peregrine: Pre-clinical Data at AACR Points to Broader Phosphatidylserine Platform [ie, “Betabodies”]; Regulatory Clarity for Bavituximab in NSCLC Could Emerge This Year”
Pre-clinical investigators recently presented data at AACR from studies of bavituximab (Bavi) and a novel phosphatidylserine targeting fusion-protein construct "betabodies”. Data generated with the KL15 betabody indicate a ~5x longer half-life vs. the mouse Bavi, and localization to tumor vasculature and inflammatory cells in mice. We believe this data represents the tip of the spear of what may be a new platform with potentially superior performance and broader lipid-targeting applicability…
Betabodies a tested approach, applied to a novel target. The most impactful data presented at AACR, in our view, could be that describing the betabody fusion-protein. The betabody KL15 consists of a fusion of domains I & V from the phosphatidylserine (PS) binding protein beta2-glycoprotein 1 (B2GP1) with the CH2 & CH3 constant domains of a mouse IgG2a antibody. We note this is a somewhat similar approach to receptor-Fc fusions that can be used to bind soluble growth factors present in the blood stream, such Regeneron’s “trap” proteins that target molecules like VEGF and others. Due to the typical high-binding affinities between a receptor and its ligand, these constructs often possess high affinity as well as long durability due to the stability of the antibody domain.
= = = = = = = =PATENTS:
‘BETABODIES’ patent app #20060228299, filed 1-24-2006, pub 10-12-2006
"Constructs Binding to Phosphatidylserine and Their Use in Disease Treatment" ("Betabodies & Receptorbodies”)
Inventors: Philip E. Thorpe, Troy A. Luster, Steven W. King
Assignee1: BOARD OF REGENTS, UNIV. OF TEXAS SYSTEM, 201 W. 7TH ST, AUSTIN, TX
Assignee2: PEREGRINE PHARMACEUTICALS, INC., 14272 FRANKLIN AVE, TUSTIN, CA
USPTO: http://tinyurl.com/649986
ABSTRACT: “Disclosed are new phosphatidylserine binding constructs with surprising combinations of properties, and a range of diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine targets in disease and enhance their destruction, and can also specifically deliver attached imaging or therapeutic agents to the disease site. Also disclosed are methods of using the new construct compositions, therapeutic conjugates and combinations thereof in tumor vasculature targeting, cancer diagnosis and treatment, and for treating viral infections and other diseases.”
[0015] ReceptorBodies & BetaBodies: The invention first provides a range of phosphatidylserine binding construct compositions, in which the constructs comprise at least a first phosphatidylserine binding protein, polypeptide or receptor operatively attached to at least a first antibody Fc region. Joining a phosphatidylserine binding protein, polypeptide or "receptor" to an "antibody" Fc region gives rise to the terms "receptorbody" and "receptorbodies", which are used herein to refer to the phosphatidylserine-binding Fc constructs of the invention.
- - - - - - - - - - - - - - -MORE:
Dr. Thorpe's LAB TEAM (UTSW Hamon Center): http://tinyurl.com/yuxemu
…2013: Thorpe lab taken over by UTSW’s Dr. Rolf Brekken: http://www.utsouthwestern.edu/labs/brekken
Dr. Thorpe's Patents: GRANTED: http://tinyurl.com/m232k PENDING: http://tinyurl.com/845p2
Dr. Thorpe's Articles: http://tinyurl.com/csjsl Also see: http://www.researchgate.net/profile/Philip_Thorpe
Dr. Alan Schroit's Patents (MDA, PPHM SRB, “Clipped B2GP1”): GRANTED: http://tinyurl.com/n4pnk8p PENDING: http://tinyurl.com/mrf2nsb
DR. SCHROIT’s ARTICLES: http://tinyurl.com/lqbd8kt Also see: http://tinyurl.com/lx2p32b (MDA profile)
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PR 7-9-07: Peregrine Licenses MDA’s “Clipped B2GP1” (invented by MDA’s Dr. Alan Schroit, PPHM SRB member – this is the basis for PS-targeting “BetaBodies” – ie, 2nd-gen. Bavi)…
…Dr. Schroit: “Clipped forms of B2GP1 may represent an exciting new approach for anti-angiogenesis therapies, and I am pleased to be collaborating with Peregrine to further explore its clinical utility. The more we learn about this plasma protein, the more intriguing its role appears to be. The anti-angiogenic potential of B2GP1 was first identified by my lab in studies suggesting that it is a negative regulator of angiogenesis that can inhibit the growth of primary tumors and metastases. 1st-Gen. anti-angiogenesis agents have already demonstrated their value in some cancer and ophthalmology applications, and we are eager to learn more about the clinical potential of this new anti-angiogenesis approach."
“Peregrine Acquires Worldwide (Exclusive) Rights to Novel Anti-Angiogenesis Technology From M. D. Anderson Cancer Center”
• “all forms of ‘clipped’ (or nicked) Beta 2 Glycoprotein 1 (B2GP1) protein”
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21055309
Correct PR link: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=266033
= = = = = = = AACR2007 (1st ‘Betabodies’ mention):
#4089 (4-17-07) ”Fusion Proteins Composed of Mouse Igg2a Fc & Mouse B2GP1 Bind to Endothelial Cells with Exposed Phosphatidylserine” [‘BETABODIES’]
Troy A. Luster, Philip E. Thorpe - UTSW-MC/Dallas
FULL ABSTRACT (JBM 3-14-07 iHub): http://www.investorshub.com/boards/read_msg.asp?message_id=17860821
” A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane under normal conditions. We have previously shown that PS becomes exposed on the surface of viable endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, a murine monoclonal antibody (3G4) was developed. 3G4 specifically localizes to the vasculature of solid tumors and inhibits growth of murine and human tumor xenografts. A chimeric version of 3G4 (bavituximab) is currently in clinical trials for treatment of solid tumor malignancies.
Recently we determined that 3G4 recognizes PS through the formation of a complex with plasma protein beta-2-glycoprotein 1 (B2GP1) b2GP1 is a 50 kDa glycoprotein composed of five domains, including the positively charged domain V that binds anionic phospholipids. However, the interaction of b2GP1 with anionic phospholipids is weak under physiological conditions. Importantly, we demonstrated that 3G4 enhances the avidity of b2GP1 for membrane surfaces with exposed PS through the formation of multivalent 3G4/b2GP1/PS complexes. This increased avidity of b2GP1 for PS is likely responsible for targeting of 3G4 to tumor EC with exposed PS.
We report here the construction of recombinant fusion proteins composed of mouse IgG2a Fc and mouse b2GP1. The Fc region is fused to the N-terminus of full-length b2GP1 or domain V only. This orientation was chosen to avoid interference with the lipid binding region in domain V of b2GP1, which is located at the extreme C-terminus of the protein. These compounds are generated as dimers, linked via disulfide bonds in the hinge region of the Fc tags. The dimeric construction provides the increased avidity necessary for these compounds to bind EC with exposed PS; thus, they behave in vitro much like the 3G4/b2GP1 complexes described previously. These Fc-B2GP1 compounds [‘BETABODIES’] have potential as tumor therapeutic or imaging agents.”
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COMMENTARTY on Peregrine Licensing Clipped-B2GPI/’Betabodies’ from MDA in 7-2007:
7-9-2007 JBM, IHUB #15268
Bavituximab is an antibody, whose 2 "feet" (antigen binding regions) each need to grab one molecule of B2GPI in order to stick to PS. Bavituximab, (like many antiphospholipid antibodies found in people), needs a co-factor to stick to its target phospholipid. The feet of bavi stick to "domain 2" of B2GPI. B2GPI's "domain 5" is actually what sticks to PS, especially when you put together TWO B2GPI molecules - (which is what bavi does).
Bavituximab is a "beta-2-glycoprotein-I-dependent anti-phosphatidylserine antibody. Here's a simplified pic:
Now, after that was all understood, (which took some time, - please read paragraphs 233-255 of the most recent Thorpe/King/Luster patent application #20120164071, which I will paste at the bottom of this post. It's a great recap of the insights & discoveries that led to the current understanding of bavi and why it is not one of the 'bad ones')…
Anyway, after that was all understood, ideas for 2nd generation drugs became obvious, hence- BETABODIES.....
A "Betabody" is a kind of "pre-made" complex of bavi+ two B2GPI's. You see, when bavi gets put into your bloodstream, each bavi molecule needs to grab TWO B2GPI's in order to form that particular complex that is so attracted to PS. There is a finite amount of available B2GPI at any given time. There is a curve of diminishing returns that comes into play, - if too many bavi molecules were shot into you, a higher percentage of them would only find ONE B2GPI molecule, resulting in a bunch of bavi's floating around that can't find a 2nd B2GPI, which is a waste...
(Obviously one reason for all this intellectual property is to cover all the bases, the possible other ways to come up with recombinant molecules that do what bavi does)…
Anyway, the idea obviously came about of making that special complex in advance. If you can, (and you can), cut the 2 feet of an antibody off, and then glue 2 B2GPI molecules on where the feet used to be, you'd have that "bavi/two-B2GPI complex" all set up to go, in advance, and taking that bell-curve of PS binding out of play.
FURTHERMORE… If you'll read the most recent patent application#20120164071 [ http://tinyurl.com/y8xuur ], you'll see how important it is for PPHM to have gotten the rights for nicked B2GPI, in as much as it looks like another next generation drug may simply be two of the B2GPI's themselves linked together, or nicked bits or two of the PS-binding regions of B2GPI linked together, or any of who knows how many other possible combinations of various domains of B2GPI that can be designed to stick well to PS...
FOR INSTANCE - in the recent patent application, there's info on:
An artificial dimeric .beta.2GPI construct binds endothelial cells with exposed PS... The patent application, (the 'betabody' patent application) is a great read if you're interested. It would help folks see the connections/logic/progress between bavi, bit's of bavi, B2GPI, & various cleaved/nicked forms of B2GPI and all the possible combinations...
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21062715
7-9-2007 BIG-TARVY, IHUB #15268
Our Lead in Anti-PS field is Confirmed.
Jazz made the understatement of the year:
“FURTHERMORE.............
If you'll read the most recent patent application, YOU’LL SEE HOW IMPORTANT IT IS FOR PPHM TO HAVE GOTTEN THE RIGHTS FOR NICKED B2GPI, in as much as it looks like another next generation drug may simply be 2 of the B2GPI's themselves linked together, or nicked bits or 2 of the PS-binding regions of B2GPI linked together, or any of who knows how many other possible combinations of various domains of B2GPI that can be designed to stick well to PS...”
As Jazz points out, M.D. Anderson could have gone to any BP or BB and sold their B2GP1 innovations for big bucks as a way to circumvent PPHM’s monopoly in the anti-PS arena.
But they did not do this. Instead, they chose to ride the future of B2GP1 EXCLUSIVELY with PPHM. Was this because of:
• the headstart PPHM has in the clinic?
• or the unique properties of 3G4 as the ideal construct for B2GP1 to bind to?
• or the strength of PPHM’s anti-PS patent portfolio?
• or the strength of PPHM’s scientists and know-how in the anti-PS field?
It doesn’t really matter which of these reasons was the dominant reason for MDA’s decision. The point is that very credible scientists at MDA, owning rights to a key component of the ultimate anti-PS platform, chose to consolidate their technology with our technology.
When analyst coverage starts, today’s license will be presented as a major reason why the BP & BB barriers to entry in the anti-PS field are so high. It seems we now have a lock on both the first-generation and the 2nd-gen. lines of anti-PS drugs.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=21070033
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